Inter-individual and sex differences in pain responses are recognized but their mechanisms are not well understood. This study was intended to provide the behavioral framework for analyses of pain mechanisms using fear extinction learning as a predictor of phenotypic and sex differences in sensory (mechanical withdrawal thresholds) and emotional-affective aspects (open field tests for anxiety-like behaviors and audible and ultrasonic components of vocalizations) of acute and chronic pain. In acute arthritis and chronic neuropathic pain models, greater increases in vocalizations were found in females than males and in females with poor fear extinction abilities than females with strong fear extinction, particularly in the neuropathic pain model. Female rats showed higher anxiety-like behavior than males under baseline conditions but no inter-individual or sex differences were seen in the pain models. No inter-individual and sex differences in mechanosensitivity were observed. The data suggest that vocalizations are uniquely suited to detect inter-individual and sex differences in pain models, particularly in chronic neuropathic pain, whereas no such differences were found for mechanosensitivity, and baseline differences in anxiety-like behaviors disappeared in the pain models.
The dopaminergic system is involved
in the regulation of immune
responses in various homeostatic and disease conditions. For conditions
such as Parkinson’s disease and multiple sclerosis (MS), pharmacological
modulation of dopamine (DA) system activity is thought to have therapeutic
relevance, providing the basis for using dopaminergic agents as a
treatment of relevant states. In particular, it was proposed that
restoration of DA levels may inhibit neuroinflammation. We have recently
reported a new class of dopamine transporter (DAT) inhibitors with
high selectivity to the DAT over other G-protein coupled receptors
tested. Here, we continue their evaluation as monoamine transporter
inhibitors. Furthermore, we show that the urea-like DAT inhibitor
(compound 5) has statistically significant anti-inflammatory
effects and attenuates motor deficits and pain behaviors in the experimental
autoimmune encephalomyelitis model mimicking clinical signs of MS.
To the best of our knowledge, this is the first study reporting the
beneficial effects of DAT inhibitor-based treatment in animals with
induced autoimmune encephalomyelitis, and the observed results provide
additional support to the model of DA-related neuroinflammation.
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